Device for delivering medicines by transpalpebral electrophoresis

ABSTRACT

The invention concerns a device for ocular application of an active principle ( 1 ) comprising a main electrode ( 2 ) including an insulating layer, an adhesive layer designed to bind the insulating layer to a conductive layer, characterized in that the main electrode comprises a zone ( 21, 22 ) designed to be urged into contact with an eyelid.

The invention concerns devices for delivering active substances inparticular by transpalpebral iontophoresis.

Iontophoresis uses electric current to enable the diffusion of anionised molecule through a biological membrane for therapeutic purposes.Under the effect of the electric current, the permeability of thebiological membrane is increased, which allows the passage of largermolecules within the cell, and the electric field pushes the moleculesthrough this membrane. This technique has the advantage compared with aconventional topical application of increasing the depth of penetrationof the active substance in proportion to the current intensity used andthe application time.

The present techniques for delivering active substances in the region ofthe eye can be classified into five categories described as follows:

-   -   the systemic route (oral route or intravenous route), sometimes        by bolus (large dose, short duration) does not give high        concentrations in the eye (less than 1%) since the blood vessels        of the retina and other parts of the central nervous system are        relatively impermeable to many active substances. Moreover,        drugs used by the systemic route can have significant secondary        effects on organs of the body other than the one explicitly        targeted;    -   direct injections around the eye into the periocular spaces or        the vitreous body are highly traumatising. Moreover, after        injection into the vitreous body, the drug is quickly diluted        and disappears in a few hours. This administration mode has        certain risks such as risks of infection, bleeding, cataract or        detachment of the retina. These problems can be partially solved        by intra-ocular implants for programmed release of active        substances implanted directly into the vitreous body, solid or        semi-solid implants, sutured or not, which require a surgical        operation to implant them and a second operation to withdraw        those made of non-biodegradable materials;    -   topical applications by drops apply only to active products that        can be formulated as a collyrium (solution or suspension) and        cannot treat the posterior segment of the eyeball since        penetration of the active substance is very limited and does not        allow therapeutic concentrations to be achieved beyond the        anterior segment of the eyeball. Furthermore, as tears wash away        the drug quickly, the applications must be repeated frequently.        It is possible to overcome these problems by using a        conjunctival insert allowing a programmed release of active        substances, whilst increasing the time of contact of the active        substance with the ocular surface. This solution has the        drawback of having a poor tolerance and a small benefit since it        proves impossible to obtain high concentrations of active        substance in the posterior segment of the eye (retina, optic        nerve);    -   photodynamic therapy is a technique which consists of        systemically injecting an active substance and activating it        locally using a laser having a certain wavelength. The major        drawback of this therapy is that the patient must remain in the        dark for several days, the active substance must be modified by        the addition of agents, a photosensitive one inhibiting its        activity until the laser activates it, the other allowing it to        be fixed on specific biological compounds in the human body.        This modification therefore supposes that the active substance        is fully tested pharmaceutically before it is put on the market,        even if it is a known medication. Finally the doctor must have        available relatively expensive equipment in the acquisition of a        specific laser;    -   finally, there are ocular iontophoresis devices like the one        indicated in patent U.S. Pat. No. 6,154,671 which describes an        iontophoresis device whose reservoir comprising the active        substance comes into direct contact with the eyeball. Such a        device makes it possible to obtain concentrations and        intra-ocular residence times equal to or greater than the        techniques previously cited, whilst being non-invasive. However,        the technique presented in this document remains tricky to use        for long-term treatments and cannot be used when the surface of        the eyeball is affected.

In the field of regional anaesthesia, outside the general anaesthesianecessary for long durations or non-cooperative patients, there are fourtechniques which concern the eyeball:

-   -   topical anaesthesia consists of instilling the anaesthetic        topically into the conjunctival sacs. This technique gives an        anaesthesia which is short but sufficient for many operations,        but of poorer quality, since there is more ocular mobility, and        it leads to an increase in postoperative pain. During the use of        this technique, use is often made of sedatives administered        intravenously and possibly leading to complications such as        respiratory arrest. In this case, the presence of an        anaesthetist is strongly recommended;    -   retrobulbar anaesthesia consists of injecting the anaesthetic        using a needle at the rear of the eyeball, inside the space        formed by the oculomotor muscles. This anaesthesia technique has        risks of perforation of the eyeball itself, risks of retrobulbar        haemorrhage, risks of injuries to the optic nerve, risks of        cardiac or respiratory arrest, risks of accidental intravascular        injection of the anaesthetic, and risks of retinal vascular        occlusion. However, the quality and duration of the anaesthesia        is good;    -   peribulbar anaesthesia consists of injecting the anaesthetic        using a needle of the eyeball and outside the space formed by        the oculomotor muscles. This technique leads to the same        complications as the previous one, but less frequently, since        the penetration of the needle is less deep;    -   finally, retrobulbar anaesthesia by catheter is a technique        consisting of putting in place an epidural type catheter        (between 0.4 mm and 1 mm in diameter) using a needle, within the        retrobulbar or peribulbar space, so as to be able to inject the        anaesthetic for operations of long duration or else to        administer it continuously even postoperatively. The risks        entailed by this anaesthesia technique are identical to the two        previous ones.

An aim of the present invention is to provide a device for deliveringocular active substances which is very simple to use and capable oftargeting the anatomical areas of the eye to be treated whilst beingnon-invasive.

For this there is provided, according to the invention, a device forocular application of an active substance comprising a main electrodecomprising an insulating layer and an adhesive layer able to bond theinsulating layer to a conductive layer, the main electrode also havingan area able to come into contact with an eyelid.

Thus, the main electrode is placed directly on the eyelid of the eye tobe treated. It thus makes it possible to treat the area of the sclerawhich is the most permeable and which has the least risk, for vision(since there is no functional retina inside the eye around the cornea).Furthermore, the functional electrode does not come into direct contactwith the eyeball. The device relies on the fact that the thickness ofthe skin at the eyelid is the smallest in the organism. Thus, thepatient can use the device on their own without requiring the presenceof a doctor, which is advantageous for iontophoreses of very longduration which have to be performed (up to 18 hours). This makes itpossible to treat pathologies of the ocular adnexa and glands of theeyelids. Abnormalities of the palpebral glands are responsible forabnormalities or reduction of the quality of the tear film, andresponsible for pathologies of the ocular surface.

Advantageously, the device for ocular application of an active substancehas at least one of the following characteristics:

-   -   the main electrode is of oval overall shape;    -   the oval shape of the electrode has a large external diameter        equal at most to approximately 40 mm and a small external        diameter equal at most to approximately 35 mm;    -   the area has a non-functional central area surrounded by a        functional peripheral area;    -   the non-functional central area is of circular shape;    -   the circular shape of the non-functional central area has a        diameter equal at most to approximately 13 mm;    -   the non-functional central area is a hole passing through the        electrode;    -   the main electrode is flexible;    -   the main electrode has in addition a cutaneous adhesive layer;    -   the main electrode has in addition a foam layer bonded to the        conductive layer by a conductive adhesive layer;    -   the foam layer is an absorbent layer able to act as a reservoir        for the active substance;    -   the insulating layer is a rigid casing; and    -   the active substance is applied by iontophoresis.

There is also provided according to the invention an electrodecomprising an insulating layer and an adhesive layer able to bond theinsulating layer to a conductive layer, characterised in that it has anon-functional central area surrounded by a functional peripheral areaable to come into contact with an eyelid.

There is also provided according to the invention a method of ocularapplication of an active substance comprising steps of placing amedication reservoir comprising a main electrode on the eyelids, placinga return electrode on the tissues adjacent to the eyeball to be treated,and penetration through the eyelid of the active substance under theeffect of a current of energy circulating between the electrodes.

Advantageously, the method has one of the following characteristics:

-   -   prior to the placing of the active electrode on the eyelids, the        active substance is disposed under the eyelids;    -   the main electrode has at least one of the aforementioned        characteristics;    -   the active substance is in a topical form (liquid, suspension,        gel);    -   the active substance is in the form of an insert.

Other characteristics and advantages of the invention will emerge fromthe description of one embodiment and variants. In the accompanyingdrawings:

FIG. 1 is a schematic depiction of a device for application of an ocularactive substance according to the invention;

FIG. 2 is a depiction in top view of a main electrode according to theinvention;

FIG. 3 is a schematic depiction in section of he main electrode of FIG.2;

FIG. 4 is a schematic depiction in section of the main electrode of FIG.2 according to a variant implementation;

FIGS. 5 a and 5 b depict a first variant implementation of a device forapplication of an ocular active substance according to the invention;

FIGS. 6 a, 6 b and 6 c depict a second variant implementation of adevice for application of an ocular active substance according to theinvention; and

FIG. 7 depicts a third variant implementation of a device forapplication of an ocular active substance according to the invention.

With reference to FIG. 1, a description will be given of the device forocular application of an active substance by iontophoresis according tothe invention.

The device 1 comprises a current generator 4 connected on the one handto a return electrode 3 and on the other hand to a main electrode 2.

The current generator 4 delivers a DC current between 0.5 mA and 5 mApreferably, perhaps even up to 10 mA, for a time between approximately0.5 and approximately 30 minutes preferably, perhaps even up toapproximately 18 hours. According to the electrical resistance of thetissues forming the circuit, a resistance liable to change during theiontophoresis, the voltage delivered by the generator is adaptedaccording to Ohm's law, U.=R.I, where U is the voltage in volts and Rthe total resistance of the circuit in ohms and I the chosen current inamperes. However the voltage delivered by this current generator cannever exceed 80 V. The use can be envisaged of an alternating currentgenerator so as to avoid an increase in pH under the effect of anoxidation-reduction phenomenon at the electrode, in particular in thecase of lengthy treatment. The frequency range of these currents ischosen in order to allow a maximum increase in the permeability of thetissues of the active substance. In this particular case, the returnelectrode 3 must be of electrocardiogram type and consisting of anadhesive and an Ag/AgCl film of low impedance. Finally, the generatorcan use a current profile having very high voltage peaks, between 50 Vand 2500 V approximately, over very short durations of the order of 0.01to 0.1 seconds, at low current (like those described forelectroporation).

It is possible to use other modes making it possible to improve thepermeability of biological membranes: magnetophoresis which usesmagnetic fields, radiofrequency and microwave electromagnetic energy, orultrasound energy. Preferably, a device according to the invention usesiontophoresis or electroporation.

With reference to FIG. 2, the overall shape of the main electrode 2 isoval. Preferably, its large external diameter corresponds substantiallyto the large diameter of the eye socket, that is approximately 40 mm.Similarly, its small external diameter corresponds to the small diameterof the socket, that is approximately 35 mm. These dimensions correspondto the standard adult size of the socket. Other sizes and shapes can beenvisaged depending on the age and morphology of the patient to betreated.

The electrode 2 has a central non-functional area 21. Preferably, thisnon-functional central area will be circular in shape with a diametercorresponding substantially to the diameter of the cornea, that isapproximately 13 mm. Preferentially, the electrode comprises a centralthrough hole acting as a non-functional area 21.

The functional peripheral area surrounding the central non-functionalarea has two sub-areas 22 and 23. The functional sub-area 22 is able tocome opposite the surface of the sclera situated around the cornea.Similarly, the functional sub-area 23 is able to cover the surface ofthe eyelid where the oculomotor muscle attachments are situated.

This particular shape of the main electrode 2 makes it possible, duringuse, to cover the maximum surface area of the sclera around the corneaand the maximum surface area of the eyelid where the oculomotor muscleattachments are situated. It should be noted that the surface of thesclera situated around the cornea is the most permeable and presents theleast risk for vision since there is no retina inside the eye aroundsaid cornea.

In general terms the main electrode 2 is flexible. Thus, the mainelectrode 2 conforms to the eyelid when it is put in place so as toassume the shape of the palpebral tissues as closely as possible andthus allow good electrical contact with the eyelid.

In another embodiment depicted in FIG. 4, the electrode 2 can be rigid.In this case, it is in the form of a casing 320 whose internal face iscoated with a flexible material 360 able to absorb anatomicaldifferences, so as to assume the shape of the palpebral tissues asclosely as possible and thus allow good electrical contact.

The structure of the electrode will now be described with reference toFIG. 3. This depicts, in section, the six layers of material possiblyconstituting the electrode, certain of these layers being optional aswill be seen. Each of these layers of material has a precise function.

The first layer 32 is an insulating layer. This is the part of the mainelectrode 2 which is able to be in contact with the operator. It makesit possible to insulate the rest of the electrode therefrom. This layercan be flexible and flat or else rigid and in the form of a casing.

The layer 33 is an adhesive layer which provides the function of bondingbetween the insulating layer 32 and a conductive layer 34 describedbelow. Furthermore, this adhesive layer 33 makes it possible to hold onthe conductive layer 34 an electric lead 31 connecting the mainelectrode 2 to the generator 4.

The layer 34 is a conductive layer. This layer consists of a silver filmand a carbon film and has the function of distributing the electriccurrent over the entire surface of the functional area of the mainelectrode 2. The silver film of this conductive layer is situated facingthe adhesive layer 33. It allows good distribution of the current overthe surface of the carbon film and provides an optimum electricalcontact with the electric lead 31. For its part, the carbon film isdisposed facing an absorbent foam layer 36 described below. This carbonlayer resists oxidation in an aqueous medium under a DC electriccurrent. The most suitable material is silver/carbon film with athickness of 0.2 mm (Rexam conductive film, reference 2252, from RexamImage Products).

The layer 36 is an optional layer. It is an absorbent foam layer able tobe impregnated with the active substance or with a solution comprisingthe active substance before use. For this reason, this absorbent foamlayer must be highly absorbent and comprise pores of small dimensions ofthe order of 100 to 500 micrometres. The most suitable material is, forexample, open-cell hydrophilic polyurethane foam of low density of theorder of 0.05 to 0.1 g/cM³ (Hydrocrest™ from Crest Foam Ind, Capu-cell®from TMP Technologies inc., Amrel® from Rynel, Medicell™ Foam fromHydromer). This layer is optional depending on whether the activesubstance is placed in the foam before use or placed directly under theeyelid before the electrode is put in place on the eyelid.

This absorbent foam layer 36 is bonded to the carbon film of theconductive layer 34 by a conductive adhesive layer 35. This conductiveadhesive must not be soluble in water.

Finally, the layer 37 is a cutaneous adhesive layer. This layer isoptional depending on whether the main electrode is adhesive or not. Thetype of adhesive chosen must conduct electric current on the one handand must allow the passage of the active substance whilst adhering aslittle as possible to the skin in order to be able to be removed easilyafter use. This cutaneous adhesive layer can be situated on theabsorbent foam layer if the latter is present or else directly on thecarbon film of the conductive layer 34.

One of the variant implementations consists of replacing the adhesivelayer 33, conductive layer 34 and conductive adhesive layer 35 by asingle conductive adhesive layer (ARcare® 8881 from Adhesive ResearchInc.) which advantageously fulfils all the aforementioned functions.

The first embodiment of the main electrode 2 is a flexible electrodecomprising a cutaneous adhesive layer 37, a conductive layer 34, anadhesive layer 33 and an insulating layer 32.

The second embodiment of the main electrode 2 is a flexible electrodecomprising a cutaneous adhesive layer 37, an absorbent foam layer 36, aconductive adhesive layer 35, a conductive layer 34, an adhesive layer33 and an insulating layer 32.

The third embodiment of the main electrode 2 is a rigid electrode in theform of a casing comprising a cutaneous adhesive layer 37, a foam layer36 acting as a flexible material intended to absorb anatomicaldifferences and assume the shape of the palpebral tissues as closely aspossible during use, a conductive adhesive layer 35, a conductive layer34, an adhesive layer 33 and a rigid insulating layer 32 forming thecasing.

Finally, the fourth embodiment of the main electrode 2 is identical tothe third embodiment described above, the foam layer being replaced bythe absorbent foam layer 36.

A description will now be given of the use of the electrode and itsdevice according to the invention.

Within the context of the first and third embodiments of the mainelectrode 2, the operator, who can be a doctor or the patient himself,disposes the active substance or a solution comprising the activesubstance under the eyelid of the eye to be treated, and then places themain electrode 2 on the eyelid and the return electrode 3 on theadjacent tissues of the eyeball to be treated. The electrodes are nextconnected to the generator and the circuit assembly is powered accordingto a defined current and a defined application time. Then, theelectrodes are removed.

In the case of the second and fourth embodiments of the main electrode2, the operator soaks the absorbent foam layer with the active substanceor a solution comprising the active substance. Then he positions themain electrode on the eyelid of the eyeball to be treated and places thereturn electrode on the tissues surrounding the eyeball to be treated.Next the operator performs the same operations as described previously.

The various medications or active substances able to be administered bya device according to the invention are those requiring regularapplication or application over a long period. This is the case, forexample, of corticosteroids or non-steroidal anti-inflammatories(dexamethazone, methylprednisolone hemisuccinate, etc.) whoseadministration must be continued over very long periods in cases ofchronic inflammation.

There are also anti-allergens, neuroprotectors, neuromodulators,anti-glaucoma agents, antibiotics, antiangiogenic agents, neurotropicfactors, and anaesthetics. Many other molecules are in the process ofbeing developed for slowing down, perhaps even halting, theneovascularisation observed in degenerative pathologies of the retina.The molecules can be transferred by the transcleral route byiontophoresis or by vitreal injection and then iontophoresis. Theiontophoresis device according to the invention makes it possible tosimplify the administration of these medications as has been possible tosee above.

Another indication of the device for application of an active substanceaccording to the invention concerns local anaesthesia of the eyelid orthe oculomotor muscles situated in the socket, which are six in numberand which allow rotational movements of the eye. These are the internalrectus muscle, the external rectus muscle, the superior rectus muscle,the inferior rectus muscle, the superior oblique muscle and the inferioroblique muscle. To these are added the levator muscle of the eyelid andthe orbicularis oculi muscle (can be of interest for aesthetic surgery,the treatment of exophthalmoses or ptoses). This indication allowsimmobilisation of the eyelid and/or akinesia of the eye within thecontext of surgical operations.

Other uses of the device for ocular application of an active substanceaccording to the invention concern active substances not requiring arecurrent application but which cannot be administered by a devicehaving direct corneal or scleral contact for a physiological reason suchas, for example, a traumatism of the surface of the eyeball or followingafter-effects of a surgical nature. Amongst the active substancesdetermined, there can be cited antibiotics, antivirals,anti-inflammatories or antimycotics for example.

Of course, many modifications can be made to the invention without forall that departing from the scope thereof.

For example:

-   -   The return electrode 3 disposed on the tissues adjacent to the        eyeball can be connected to the main electrode 2 by means of a        non-conductive film 50 and disposed on the temple of the patient        to be treated as illustrated in FIGS. 5 a and 5 b.    -   There can be two main electrodes 2 (one for each eye), disposed        on a mask 100 (such as a sleeping mask used in air transport for        example), the return electrode 3 associated with the generator        (component 43) can be placed on the forehead of the patient        preferentially, and connected to the main electrodes by means of        electric leads 31, as illustrated in FIG. 6 a. It should be        noted that the mask 100 is held on the head of the patient by        elastic means such as a headband.    -   In a variant illustrated in FIG. 6 b of the arrangement        described previously, a return electrode and the generator        (component 43) can be placed advantageously inside the elastic        headband for holding the mask 100 comprising the two main        electrodes 2, so that the return electrode is on one of the        temples (or else both in a variant disposition where there are        two return electrodes). Here, the elastic holding means also        serves as an electric lead which is implemented in the form of        conductive tracks for example.    -   FIG. 6 c illustrates a pair of spectacles 120 comprising two        main electrodes 2 situated in place of the lenses of the pair of        spectacles 120. A generator 4 is installed on the frame of the        pair of spectacles 120 and connected, on the one hand, to the        two electrodes 2 and, on the other hand, to the return        electrodes 30 which are, preferably, situated beneath the main        electrodes 2 so as to be in contact (whilst being insulated from        these main electrodes) with the skin of the top of the cheeks of        the patient or situated on the ends of the side-pieces of the        pair of spectacles 120 so as to be in contact with the skin        situated behind the ears of the patient.    -   FIG. 7 illustrates another variant implementation in which the        two main electrodes 2 are mounted on a cap 110, as is the        component 43 comprising the generator and the return electrode.

In the last four variants illustrated in FIGS. 6 a, 6 b, 6 c and 7, thereturn electrode can be placed on the tissues of the face surroundingthe eyeball such as the temples, the forehead, the cheeks, etc., ingeneral terms. Furthermore, the generator can be associated therewith ornot. It is possible, in variants, to place at a distance the generatorconnected to the main 2 and return 3 electrodes by means of electricalwires. In the contrary case, the connecting wires are integrated withthe device in the form of conductive tracks for example.

These four embodiments are well adapted for treating degenerativepathologies such as diabetic retinopathy, macular degeneration relatedto age, and pigmentary retinitis. This is because it is known, for thesepathologies, that the probability that both eyes are affected is high(of the order of 50% of cases). In this case, it is necessary to treatboth eyes at the same time or over one and the same time intervalalternately.

1. A device for ocular application of an active substance comprising amain electrode, the main electrode comprising: (i) an insulating layer,(ii) a conductive layer, (iii) an electric lead sandwiched between theinsulating layer and the conductive layer, wherein the electric lead isconfigured for connecting the main electrode to an external electricalfeeding source, (iv) an adhesive interlayer comprising material havingadhesive properties for bonding the insulating layer to the conductivelayer and for holding the electric lead onto the conductive layer, and(v) a foam layer bonded to the conductive layer by a conductive adhesivelayer, wherein the foam layer is an absorbent foam layer able to act asa reservoir for the active substance, wherein the main electrodecomprises a functional area configured to substantially cover an outersurface of an eyelid and which delivers the active substance through theeyelid onto the sclera of the eyeball and a non-functional central area.2. A device according to claim 1, wherein the main electrode is of ovaloverall shape.
 3. A device according to claim 2, wherein the oval shapehas a large external diameter equal at most to approximately 40 mm and asmall external diameter equal at most to approximately 35 mm.
 4. Adevice according to claim 1, wherein the non-functional central areaoverlays the cornea of a subject and the surrounding functionalperipheral area overlays the area of the eye of the subject peripheralto the cornea when the electrode is placed in contact with the eyelid ofa subject.
 5. A device according to claim 4, wherein the non-functionalcentral area is of circular overall shape.
 6. A device according toclaim 5, wherein the non-functional central area has a diameter equal atmost to approximately 13 mm.
 7. A device according to claim 4, whereinthe non-functional central area is a hole passing through the mainelectrode.
 8. A device according to claim 1, wherein the main electrodefurther comprises: (vi) a cutaneous adhesive layer.
 9. A deviceaccording to claim 1, wherein the main electrode further comprises: (vi)the conductive adhesive layer sandwiched between the foam layer and theconductive layer, comprising water insoluble material having adhesiveproperties for bonding the foam layer to the conductive layer.
 10. Adevice according to claim 1, wherein the main electrode is flexible. 11.A device according to claim 1, wherein the insulating layer is a rigidcasing.
 12. A device according to claim 1, wherein the active substanceis applied by iontophoresis.
 13. A device according to claim 1, whereinthe absorbent foam layer is an open-cell hydrophilic polyurethane foam.14. A device according to claim 13, wherein the absorbent foam layer hasa density of 0.05 to 0.1 g/cm
 3. 15. An electrode for the ocularapplication of an active substance comprising a main electrode, the mainelectrode comprising: (i) an insulating layer, (ii) a conductive layer,(iii) an electric lead sandwiched between the insulating layer and theconductive layer, connecting the main electrode to an externalelectrical feeding source, (iv) an adhesive interlayer comprisingmaterial having adhesive properties for bonding the insulating layer tothe conductive layer and for holding the electric lead onto theconductive layer, (v) a foam layer, wherein the foam layer is anabsorbent foam layer able to act as a reservoir for the activesubstance, (vi) a conductive adhesive layer sandwiched between the foamlayer and the conductive layer, comprising water insoluble materialhaving adhesive properties for bonding the foam layer to the conductivelayer, and (vii) a cutaneous adhesive layer adjacent to the foam layerand having adhesive properties for bonding the main electrode to theouter surface of the eyelid, wherein the electrode comprises afunctional area configured to substantially cover an outer surface of aneyelid and which delivers the active substance through the eyelid ontothe sclera of the eyeball and a non functional central core.